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Impact of selective decontamination of the digestive tract on carriage and infection due to Gram-negative and Gram-positive bacteria: a systematic review of randomised controlled trials.

SUMMARY

Mete-analyses of randomised controlled trials of selective digestive decontamination have clinical outcome measures, mainly pneumonia and mortality. This mete-analysis has a microbiological endpoint and explores the impact of selective digestive decontamination on Gram-negative and Gram-positive carriage and severe infections We searched electronic databases Cochrane Register of Controlled Trials, previous mete-analyses and conference proceedings with no language restrictions. We included randomised controlled trials which compared the selective digestive decontamination protocol with no treatment or placebo. Three reviewers independently applied selection criteria, performed the quality assessment and extracted the data. The outcome measures were carriage and severe infection due to Gram-negative and Gram-positive bacteria. Odds ratios were pooled with the random effect model. Fifty-four randomised controlled trials comprising 9473 patients were included, 4672 patients received selective digestive decontamination and 4801 were controls Selective digestive decontamination significantly reduced oropharyngeal carriage (odds ratio [OR] 0.13, 95% confidence interval [CI] 0.07 to 0.23), rectal carriage (OR 0.15, 95% CI 0.07 to 0.31), overall infection (OR 0.17, 95% CI 0.10 to 0.28), lower respiratory tract infection (OR 0.11, 95% CI 0.06 to 0.20) and bloodstream infection (OR 0.35, 95% CI 0.21 to 0.67) due to Gram-negative bacteria. Reduction in Gram positive carriage was not significant. Gram-positive lower airway infections were significantly reduced (OR 0.52, 95% CI 0.34 to 0.78). Gram-positive bloodstream infections were not significantly increased (OR 1.03, 95% CI 0.75 to 1.41). The association of parenteral and enteral antimicrobials was superior to enteral antimicrobials in reducing carriage and severe infections due to Gram-negative bacteria. This mete-analysis confirms that selective digestive decontamination mainly targets Gram-negative bacteria, it does not show a significant increase in Gram-positive infection.

Key Words: selective decontamination, digestive decontamination, intensive care unit, respiratory tract infection, carriage, bloodstream infection, Gram-negative, Gram-positive

The key to infection control in the intensive care unit (ICU) is to appreciate that a limited range of potentially pathogenic micro-organisms, both 'normal', including Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus; and 'abnormal', such as aerobic Gram-negative bacilli, may cause three different types of infection, each requiring a different prophylactic manoeuvre (1). Exogenous infections may be controlled by a high level of hygiene, primary endogenous infections by the immediate administration of parenteral antibiotics and secondary endogenous infections by the application of enteral antimicrobials in throat and gut (2).

Selective decontamination of the digestive tract (SDD) using hygiene and parenteral and enteral antimicrobials is a prophylactic measure aiming at the control of exogenous, primary endogenous and secondary endogenous infections, and at the reduction in mortality (1,2). Twelve systematic reviews and mete-analyses of randomised controlled trials (RCT) explored the efficacy of the prophylactic manoeuvre of SDD (3-14). The majority of them focused on a clinical endpoint, mainly pneumonia (3-10,12), bloodstream infection (7,10,14) and mortality (3-9,11,12,14). SDD significantly reduced the odds ratio for pneumonia, bloodstream infection and mortality to 0.35 (95% CI 0.29 to 0.41) (12), 0.63 (0.46 to 0.87) (14) and 0.78 (0.68 to 0.89) (12) respectively. However, none of those meta-analyses assessed the impact on the microbiology of the digestive tract carriage and only two distinguished the type of micro-organism causing infections, one included a small sample of liver transplant patients (11) and the other evaluated only patients with bloodstream infection (14). Additionally, microbiological data are required to confirm or refute the fear that the widespread use of SDD will lead to a serious Gram-positive problem.

We performed a systematic review and meta-analysis of randomised controlled trials of SDD to explore the impact of SDD on carriage and severe infections due to Gram-negative and Gram-positive bacteria.

MATERIALS AND METHODS

Identification of relevant literature and retrieval of studies

We searched Medline (January 1976 to June 2006), Embase (January 1980 to June 2006) and the Cochrane Register of Controlled Trials (June 2006). We use the search terms "intensive care unit", "critical care", "antibiotic combined therapeutic use", "antibiotic combined administration and dosages", "decontamination", "respiratory tract infection prevention and control", "bacterial infection", with the keywords "SDD", "selective decontamination", "selective digestive decontamination", "digestive decontamination", "bowel decontamination". No language restriction was applied. Additionally, we checked reference lists of previous systematic reviews and meta-analyses of SDD and all identified papers of SDD, searched conference abstracts and proceedings of scientific meetings held on the subject.

Inclusion and exclusion criteria

Inclusion and exclusion criteria were established by the investigators before reviewing abstracts and articles. We included all randomised trials comparing enteral administration of antibiotics of SDD (oropharyngeal, intestinal or both), with or without a parenteral component, with no treatment or placebo in the controls. All published and unpublished trials in unselected and selected critically ill patients were considered. RCTs with usable information by outcome were finally included in the meta-analysis. Studies were excluded for the following reasons: 1) studies including neutropaenic, stem cell and bone marrow transplant patients; 2) non-randomised studies; 3) double publications; 4) studies including data extracted from or complementing main publications; 5) both study arms received SDD but evaluated another drug; and 6) endpoint not infection.

Data extraction and quality assessment

Three investigators (LS, HKFvS, AC) independently retrieved the published findings from each study and compared the sets of data. Any disagreement was resolved by reinspection of the original data and discussion. Where data were available all randomised patients were included in the analysis, allowing an intention-to-treat analysis. The following data were sought for each study: type of population included; specific antimicrobials used and routes; number of patients in each arm; total number of carriers; number of patients with oropharyngeal and rectal carriage due to Gram-negative bacteria; number of patients with Gram-negative infection; number of patients with Gram-negative infection of the lower airways and the bloodstream. Identical variables were sought for Gram-positive bacteria.

We assessed the quality of each study according to a predefined list of seven criteria contained in a scoring system ranging from 0 to 14 and derived by Heyland et al (6), and modified (15), and previously described (14). The assessment was made by three investigators (LS, HKFvS, AC) and included randomisation, blinding, patient selection, population description, reproducibility and definitions of carriage and infection. A total score was obtained as the sum of the subscores of the three evaluators for each of the seven dimensions.

Statistical analysis

The primary endpoints were overall carrier state, patients with oropharyngeal and rectal carriage due to Gram-negative and Gram-positive bacteria, patients with overall Gram-negative and Gram-positive infections, and patients with infections of the lower airway and the bloodstream due to Gram-negative and Gram-positive bacteria.

A subgroup analysis of primary endpoints was planned a priori. To analyse the effect of SDD on the studied variables, RCTs were grouped according to: 1) type of regimen used (parenteral plus enteral or enteral only); 2) quality of randomisation procedures (adequate or inadequate); 3) blinding of patients and caregivers to allocated treatment (blinded or not-blinded); and 4) quality of the study (high or low) (16). Randomisation was adequate when patients were randomised by telephone or a central office. A study was blinded when caregivers and outcome assessors were blinded. The quality categories were obtained according to the median value of the quality scores of all studies. Moreover, an additional subgroup analysis of only infectious endpoints due to Gram-negative micro-organisms was specified a priori in order to analyse the impact of SDD in studies where successful decontamination was achieved. A successful decontamination was defined when the odds ratio (including the 95% confidence interval) for oropharyngeal or rectal or overall carriage due to Gram-negative micro-organisms was less than the unit in each study.

Results were presented as odds ratios (OR) with 95% confidence interval (CI) using the random effects model. The random effects model provides a more conservative estimate of the 95% CI, taking heterogeneity into account: 0.5 cases were added to empty cells to allow calculation of ORs. The ORs were less than the unit if the outcome occurred less frequently in the SDD group. The Cochrane Q statistic for heterogeneity was used both for the outcome measures and through subgroup analyses; we considered heterogeneity to be significant if the P value was < 0.10. We also evaluated the [I.sup.2] measure of inconsistency with the formula 100% x (Q-df)/ Q, where Q is Cochrane's Q statistics and df is the degree of freedom (number of studies-1). Negative values of [I.sup.2] were put equal to 0%, which indicated no observed heterogeneity, while larger percentages indicated increasing heterogeneity. We predefined significant heterogeneity as an [I.sup.2] measure greater than 50% (17). We examined a funnel diagram of the log of the ORs against the weight to estimate potential publication bias. Computations were performed using the EasyMA software (18).

RESULTS

Search findings and general description of the studies

We evaluated 124 potentially eligible studies (Figure 1). Of these studies, 68 were excluded: 47 studies were not randomised, 18 were double publications or included data extracted from the main publication and in three studies both arms received SDD and evaluated another drug. We identified 56 potentially appropriate RCTs. In addition, two studies were excluded because infection or carriage were not the endpoints (19,20). A final sample of 54 RCTs, which enrolled a total of 9473 patients (4672 SDD e 4801 control), was the basis for the systematic review and meta-analysis (21-74).

The details of each study are described in Table 1. One trial was split into two parts in which two different treatments were compared with the same control group (70). Data from the Lingnau's study were retrieved from an additional paper on the microbiology of the same study (75). In one study, one of the two control arms receiving only sucralfate was excluded (51). Of the 54 trials, two were published as abstract (28,37). Four trials were performed in paediatric intensive care units (24,61,64,73). Trials in specific selected types of patients included liver transplantation (23,26,44,56,64,74), burn (24,34), cardia (29,38,73) and gastric surgery (63), oesophageal resection (67), pancreatitis (51), neurosurgery (45,47,69), stroke (42) and acute liver failure (59,60).

[FIGURE 1 OMITTED]

The decontamination protocol varied among studies. Forty-three RCTs included the parenteral component, in general a third generation cephalosporin: 22 in the test arm only and 21 in both arms. In the remaining 11 RCTs including the enteral component only, five used the oropharyngeal and intestinal route, three the intestinal and three the oropharyngeal. Twenty-one RCTs were blinded (23,24,28,29,31,32,34,39,42,43,47,48,50,54,55,57,58,62,63,65,70) and in 16 studies the randomisation was adequate (25,29,31-34,42,47,48,55,57,62-64,73,74). The methodological quality assessment for all trials showed a median of 9.3 (interquartile range 8 to 11) and a weighted kappa on agreement of 0.50 (95% CI, 0.24 to 0.75).

Overall bacterial carriage

Nine studies including 1178 patients (562 SDD, 616 control) reported information on the carrier state, without citing the type of micro-organisms (21,22,24,25,33,49,50,55,58). Ninety-five patients (16.9%) of the SDD group and in 381 patients of the control group (61.8%) developed a carrier state. SDD significantly reduced the number of carriers (OR 0.11, 95% CI 0.05 to 0.26, P < 0.001). The test for heterogeneity yielded a not significant result ([[chi].sup.2] 8.97, P=0.34; [I.sup.2] 10.81%).

Carriage and infection due to Gram-native bacteria

Results from 20 RCTs including 3547 patients (1789 SDD, 1758 control) were available for the analysis of Gram-negative oropharyngeal carriage (21,26,35,36,38,42,43,45-47,50,52,57,61,63,65,68,69,71,73). There were 141 (7.9%) carriers in the SDD group and 536 (30.5%) in the controls. The results indicated a protective effect of SDD on Gram-negative carrier state of the oropharynx (OR 0.13; 95% CI 0.07 to 0.23, P <0.001) (Figure 2). The test for heterogeneity for the overall comparisons was not significant ([[chi].sup.2] 17.69, FL- 0.54; [I.sup.2] 0%).

[FIGURE 2 OMITTED]

Data on rectal carriage were retrieved from 15 RCTs including a total of 1942 patients (971 SDD, 971 control) (23,26,29,30,43,46,47,50,56,57,65,67,68,71,73). There were 69 (7.1%) carriers in the SDD group and 346 (35.6%) amongst controls. SDD significantly reduced Gram-negative rectal carrier state (OR 0.15, 95% CI 0.07 to 0.31, P <0.001). The test for heterogeneity was not significant ([[chi].sup.2] 15.41, P=0.38, [I.sup.2] 2.66%).

Eight studies comprising of 923 patients (451 SDD, 472 control) included data on overall Gram-negative infections with any report of the infection site (21,23,30,33,44,55,62,64). There were 20 (4.4%) patients with Gram-negative infections in SDD group and 89 (18.8%) in the control group. SDD significantly reduced Gram-negative infections by 83% (OR 0.17, 95% CI 0.10 to 0.28, P<0.001) (Figure 3). Heterogeneity was not found ([[chi].sup.2] 5.63, P=0.58; [I.sup.2] 0%).

Fourteen RCTs, including 759 SDD patients and 750 controls, were available for the analysis of Gram-negative lower airway infections (21,22,27,36,45,49,52,53,55,58,64,67,68,73). Twenty-four (3.2%) and 170 (22.7%) patients of the SDD and control group, respectively, developed lower airway infections. The SDD prophylaxis reduced significantly the odds of Gram-negative lower airway infection (OR 0.11, 95% CI 0.06 to 0.20, P< 0.001). The test for heterogeneity was not significant ([[chi].sup.2] 10.13, P=0.68, [I.sup.2] 0%).

[FIGURE 3 OMITTED]

There were 19 trials including 2280 patients (1134 SDD, 1136 controls) which reported data on patients with bloodstream infections due to Gram-negative micro-orgamsms (21,26,27,33,36,40,41,44,45,49,55,59,60,64,66-68,71,73) The prevalence of Gram-negative bloodstream infections was 2% (n=23) among treated patients and 7.7% (n= 87) amongst controls. The results indicated a protective effect of SDD on Gram-negative bloodstream infections (OR 0.35, 95% CI 0.21 to 0.67, P < 0.001). The test for heterogeneity for the overall comparisons was not significant ([[chi].sup.2] 16.65, P=0.65, [I.sup.2] 0%). Results are summarised in Table 2.

Carriage and infection due to Gram-positive bacteria

Table 2 shows the impact of SDD on Gram-positive carriage and infection. SDD reduced, albeit not significantly, oropharyngeal and rectal carriage and overall infections due to Gram-positive bacteria, while lower airway infections were significantly reduced (OR 0.52, 95% CI 0.34 to 0.78, P=0.0016). Gram-positive bloodstream infections were increased by SDD, but not significantly (OR 1.03, 95% CI 0.75 to 1.41, P=0.85). Heterogeneity was not found in all comparisons.

Subgroup analysis

A subgroup analysis was performed in studies including data on patients with Gram-negative oropharyngeal and rectal carriage, and Gram-negative infections, both overall, lower respiratory tract infections (LRTI) and bloodstream infections (BSI) (Table 3). In general, the association of parenteral and enteral antimicrobials was superior to only enteral antimicrobials in reducing oropharyngeal carriage, rectal carriage, overall infections, LRTI and BSI due to Gram-negative bacteria. The reduction in LRTI and BSI was superior in SDD RCTs in which a proper decontamination was obtained.

The subgroup analysis of the primary endpoints due to Gram-positive micro-organisms confirmed the previous pooled data (Table 4). Carriage and overall Gram-positive infections were reduced in the majority of comparisons, but not significantly. Similarly, bloodstream infections were reduced, albeit not significantly, in studies with adequate randomisation, unblinded and with low quality, and in studies using parenteral and enteral anti-microbials. Lower airway infections due to Gram-positive bacteria were reduced in all subgroups.

Effect of publication bias

The inspection of the funnel plots for the outcome variables provided no evidence of publication bias (data not shown).

DISCUSSION

This systematic review of 54 randomised controlled trials assessing selective digestive decontamination in approximately 10,000 patients requiring intensive care is the most comprehensive to date. In particular, this meta-analysis is the first to analyse the microbiology of the SDD-RCTs, both carriage and infection. Four important findings emerge from this meta-analysis:

* SDD significantly reduces both carriage and infections due to Gram-negative bacteria;

* The impact of SDD on Gram-negative carriage and infection using parenteral and enteral antimicrobials is greater than using only enteral antimicrobials;

* The reduction in carriage and infection due to Gram-positive micro-organisms is not significant; lower airway infections due to Gram-positive micro-organisms are significantly reduced, while bloodstream infections due to Gram-positive micro-organisms are not significantly increased;

* The reduction in serious infections is slightly superior in RCTs in which the patients are successfully decontaminated compared with the RCTs in which successful decontamination is not achieved.

This meta-analysis demonstrates that the enteral antimicrobials of SDD, polymyxin and tobramycin, protect against acquisition and secondary carriage due to Gram-negative micro-organisms transmitted via hands of carers. By design of the technique those two antimicrobials were carefully chosen, as they are synergistic against aerobic Gram-negative bacilli, in particular Psaudomonas aeruginosa (76), both respect the indigenous flora of the patients (77,78), neutralise endotoxin released by aerobic Gram-negative bacilli (79), and have a low potential for resistance (80).

Remarkably, the addition of the parenteral antibiotic, mainly cefotaxime, resulted in a more effective clearing of Gram-negative carriage, both oropharyngeal and rectal and reduction in overall Gram-negative infections, LRTI and bloodstream infections compared with RCTs using only enteral antimicrobials. Intravenous cefotaxime is excreted via saliva, bile and mucus into throat and gut, and has been shown to eradicate carriage of 'normal' potential pathogens such as S pneumoniaa S. aureus, H. influenzae and E. coli (81). The greater decontamination effect of SDD using parenteral and enteral antimicrobials may be due to the decontamination of E. coli following cefotaxime excretion in throat and gut.

Data from 56 RCTs and 12 meta-analyses do not provide any evidence for a link between SDD and the emergence of antimicrobial resistance (82). Antimicrobial resistance being a long-term issue, has been evaluated in 11 studies monitoring it between two and nine years, and bacterial resistance associated with SDD has not been a clinical problem (75, 83-92). The experts emphasised that the use of SDD was associated with a Gram-positive problem: however, their claim was mainly based on case reports" and review articles (94,96). This meta-analysis failed to confirm these assertions. Oropharyngeal and rectal carriage of Gram-positive bacteria and overall infections due to Gram-positive bacteria were reduced by SDD, albeit not significantly. More specifically, lower airway infections due to Gram-positive bacteria were significantly reduced, while Gram-positive bloodstream infections were increased, but not significantly. Parenteral cefotaxime given for the first days after admission may effectively control primary endogenous lower airway infections due to the 'community' Gram-positive respiratory pathogens, i.e. S pneumoniae and S. aureus. A substantial part of bloodstream infections are catheter-related and are caused, in general, by skin flora including coagulase-negative staphylococci, which are not influenced by the technique (14). Methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE) are two Gram-positive bacteria that are intrinsically resistant to the parenteral and enteral antimicrobials of the SDD protocol. They were endemic in the ICUs of nine RCTs (23,34,36,39,43,44,50,70,71) and may explain why the reduction in Gram-positive carriage was not significant. However, VRE carriage and infection were the primary endpoints of SDD RCTs in two American ICUs with endemic VRE (23,44): there was no significant difference between test and control groups. There are seven RCTs conducted in ICUs where MRSA was endemic at the time of the trial, they report a trend towards higher MRSA carriage and infection rates in patients receiving SDD (34,36,39,43,50,70,71). Therefore, the results of this systematic review on Gram-positive micro-organisms should be prudently interpreted, as the impact of SDD could depend on the prevalence or endemicity of Gram-positive organisms in a different study population, irrespective of the effect on Gram-negative micro-organisms.

An intriguing finding of this meta-analysis is the reduced infection rate in RCTs whether the patients were successfully decontaminated or not, i.e. were rendered free of aerobic Gram-negative bacilli or not. This reduction can only be explained by the parenteral component, cefotaxime, that virtually eliminated primary endogenous infections due to normal flora occurring within the first week after admission to the ICU. However, the reduction in infection rate was superior in RCTs in which patients were effectively decontaminated, as there were no secondary endogenous infections in patients rendered free of aerobic Gram-negative bacilli. Similarly, in surgical ICU patients, SDD was beneficial in terms of mortality rate and length of hospital stay only when successful decontamination was achieved (96-98).

We acknowledge some limitations of this review. First, the underreporting of the outcome measures may be explained by the fact that the majority of RCTs of SDD were designed to assess the impact of SDD on lower respiratory tract infections and mortality, not the patient's carrier state and the microbiology of carriage and infections. Second, the design of this review excluded urinary tract infections. Only infections of the lower airways and the bloodstream were included as they contribute to mortality (12,14). Third, the distinction between Gram-negative and Gram-positive micro-organisms was not always obtainable and episodes of infection rather than patients were frequently used in RCTs, making the calculation of the odds ratio impossible. For example, in two RCTs the number of infectious episodes in the control arm exceeded the number of patients enrolled (46,57). Fourth, this review did not include data on the impact of SDD on fungal carriage and infection. Indeed, a previous meta-analysis has demonstrated that SDD significantly reduced both carriage and overall fungal infections, albeit the reduction in fungaemia rate was not significant due to the low fungaemia rate (13). Fifth, by design this review did not distinguish between the type of Gram-negative and Gram-positive microorganism causing infections. This should be taken into account when translating the results of this analysis into clinical practice as mortality is different in severe infections due to the Gram-positive MSSA and MRSA compared with low level pathogens, such as VRE and coagulase-negative staphylococci, and due to the Gram-negative H. influenzae compared with P. aeruginosa.

In summary, this meta-analysis confirms that SDD using parenteral and enteral antimicrobials is a prophylactic protocol that targets mainly Gram-negative micro-organisms. Moreover, the reduction of the level of Gram-negative carriage leads to significantly reduced infection rates. Additionally, the opponents' assertion (99) that there is strong contravening evidence that SDD promotes infection due to Gram-positive bacteria is unsupported by this review.

Accepted for publication on February 6, 2008.

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(75.) Lingnau W, Berger J, Javorsky F, Fille M, Allerberger F, Benzer H. Changing bacterial ecology during a five year period of selective intestinal decontamination. J Hosp Infect 1998; 39:195-206.

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(79.) van Saene JJM, Stoutenbeek CP, van Saene HKF et al. Reduction of the intestinal endotoxin pool by three different SDD regimens in human volunteers. J Endotoxin Res 1996; 3:337-343.

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(83.) Hammond JM, Potgieter PD. Long-term effects of selective decontamination on antimicrobial resistance. Crit Care Med 1995; 23:637-645.

(84.) van der Voort PH, van Roon EN, Kampinga GA, Boerma EC, Gerritsen RT, Egbers PH et al. A before-after study of multi-resistance and cost of selective decontamination of the digestive tract. Infection 2004; 32:271-277.

(85.) Viviani M, van Saene HK, Dezzoni R, Silvestri L, Di Lenarda R, Berlot G et al. Control of imported methicillin-resistant Staphylococcus aureus (MRSA) on mechanically ventilated patients: a dose-response study of enteral vancomycin to reduce absolute carriage and infection. Anaesth Intensive Care 2005; 33:361-372.

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(87.) Sarginson RE, Taylor N, Reilly N, Baines PB, van Saene HK. Infection in prolonged pediatric critical illness: A prospective four year study based on knowledge of the carrier state. Crit Care Med 2004; 32:839-847.

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(89.) Leone M, Albanese J, Antonini F, Nguyen-Michel A, Martin C. Long-term (6-year) effect of selective digestive decontamination on antimicrobial resistance in intensive care, multiple-trauma patients. Crit Care Med 2003; 31:2090-2095.

(90.) de la Cal MA, Cerda E, van Saene HK, Garcia-Hierro P, Negro E, Parra ML et al. Effectiveness and safety of enteral vancomycin to control endemicity of methicillin-resistant Staphylococcus aureus in a medical/surgical intensive care unit. J Hosp Infect 2004; 56:175-183.

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(92.) Cerda E, Abella A, de la Cal MA, Lorente JA, Garcia-Hierro P, van Saene HK et al. Enteral vancomycin controls methicillin-resistant Staphylococcus aureus endemicity in an intensive care burn unit: a 9-year prospective study. Ann Surg 2007; 245:397-407.

(93.) Bonten MJ, van Tiel FH, van der Geest S, Stobberingh EE, Gaillard CA. Enterococcus faecalis pneumonia complicating topical antimicrobial prophylaxis. New Engl J Med 1993; 328:209-210.

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(95.) Kollef MIL Selective digestive decontamination should not be routinely employed. Chest 2003; 123 (5 Suppl):464S-468S.

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(99.) Kallet RH, Quinn TE. The gastrointestinal tract and ventilator-associated pneumonia. Respir Care 2005; 50:910-921.

L. SILVESTRI *, H. K. F. VAN SAENE ([dagger]), A. CASARIN ([double dagger]), G. BERLOT ([section]), A. GULLO ** Department of Emergency, Unit of Anaesthesia and Intensive Care, Presidio Ospedaliero di Gorizia, Gorizia, Italy

* M.D., Head, Department of Emergency, Unit of Anaesthesia and Intensive Care, Presidio Ospedaliero di Gorizia, Gorizia, Italy.

([dagger]) M.D., Ph.D, F.R.C.Path., Consultant/Reader, Department of Medical Microbiology, University of Liverpool and Department of Clinical Microbiology and Infection Control, Alder Hey Children's Hospital, Liverpool, United Kingdom.

([double dagger]) M.D., Clinical Fellow, Department of Critical Care, St. Michael's Hospital, Toronto, Ontario, Canada.

([section]) M.D., Head, Unit of Anesthesia, Intensive Care and Pain Therapy, University Hospital, Trieste, Italy. **M.D., Head, Unit of Anaesthesia and Intensive Care, Policlinico University Hospital, Catania, Italy.

Address for reprints: Dr L. Silvestri, Department of Emergency, Unit of Anaesthesia and Intensive Care, Presidio Ospedaliero, Via Vittorio Veneto 171, 34170 Gorizia, Italy.
TABLE 1
General characteristics of 54 randomised controlled trials of selective
decontamination of the digestive tract

Authors Population studied No. Patients

 SDD C

Abele-Horn (21) Trauma 58 30
Aerdts (22) Mixed 28 60
Arnow (23) Liver transplant 48 38
Barrette (24) Paediatric, burns 11 12
Bergmans (25) Mixed 87 139
Bion (26) Liver transplant 27 32
Blair (27) Mixed 161 170
Boland (28) Trauma 32 32
Bouter (29) Cardiac 24 27
Brun-Buisson (30) Mixed 65 68
Camus (31) Mixed 259 256
Cerra (32) Mixed 24 23
Cockerill (33) Mixed 75 75
de la Cal (34) Burns 58 59
de Jonge (35) Mixed 466 468
Ferrer (36 Respiratory 51 50
Finch (37) Mixed 24 25
Flahertye (38) Cardiac 51 56
Gastinne (39) Mixed 220 225
Gaussorgues (40) Mixed 59 59
Georges (41) Trauma 31 33
Gosneyl (42) Acute stroke 103 100
Hammond (43) Respiratory 162 160
Hellinger (44) Liver transplant 37 43
Jacobs (45) Neurosurgery 45 46
Kerver (46) Mixed 49 47
Korinek (47) Neurosurgery 96 95
Krueger (48) Surgical, trauma 273 273
Laggner (49) Mixed 33 34

Lingnau (50) Trauma 180 177

Luiten (51) Pancreatitis 54 55
Palomar (52) Trauma 59 55
Pneumatikos (53) Trauma 40 39
Pugin (54) Surgical, trauma 38 41
Quinio (55) Trauma 76 72
Rayes (56) Liver transplant 32 63
Rochas (57) Trauma 47 54
Rodriguez-Roldan (58) Mixed 14 17
Rolando (59) Liver failure 49 52
Rolando (60 Liver failure 47 61

Ruza (61) Paediatric 116 110
Sanchez-Garcia (62) Mixed 131 140
Schardey (63) Gastrectomy 102 103
Smith (64) Paediatric, liver 18 18
 transplant
Stoutenbeek (65) Trauma 49 42
Stoutenbeek (66) Trauma 201 200
Tetteroo (67) Esophagectomy 56 58
Ulrich (68) Mixed 55 57
Unertl (69) Neurosurgery 19 20

Verwaest (70) Mixed 220 220
 220 220
Wiener72 Mixed 30 31
Winter (72) Mixed 91 92
Zobel (73) Paediatric, cardiac 25 25
Zwaveling (74) Liver transplant 45 44

Authors Regimen
 Parenteral
 AGNB

Abele-Horn (21) Cefotaxime P T
Aerdts (22) Cefotaxime P Nor
Arnow (23) Cefotaxime/ampicillin 2 arms P G
Barrette (24) Pip eracillin/amikacin/van 2 arms P T
Bergmans (25) Antibiotiotic (40%) 2 arms P G
Bion (26) Cefotaxime/ampicillin 2 arms P T
Blair (27) Cefotaxime P T
Boland (28) Cefotaxime P T
Bouter (29) Flucloxacillin 2 arms Pb Neo
Brun-Buisson (30) - P Neo Nal
Camus (31) - P T
Cerra (32) - Nor
Cockerill (33) Cefotaxime Pb G
de la Cal (34) Cefotaxime P T
de Jonge (35) Cefotaxime P T
Ferrer (36 Cefotaxime 2 arms P T
Finch (37) Cefotaxime Pb G
Flahertye (38) Cefazolin 2 arms P G
Gastinne (39) Antibiotics 2 arms (65%) P T
Gaussorgues (40) Antibiotics 2 arms P G
Georges (41) Amoxicillin/clavulanate 2 arms P N
Gosneyl (42) - P T
Hammond (43) Cefotaxime 2 arms P T
Hellinger (44) Ceftizoxime 2 arms P G
Jacobs (45) Cefotaxime P T
Kerver (46) Cefotaxime P T
Korinek (47) - P T
Krueger (48) Ciprofloxacin Pb G
Laggner (49) Amoxicillin/clavulanate (70%)
 2 arms G
Lingnau (50) Ciprofloxacin 2 arms P T
 P Cipro
Luiten (51) Cefotaxime P Nor
Palomar (52) Cefotaxime P T
Pneumatikos (53) - P T
Pugin (54) - Pb Neo
Quinio (55) Cefazolin 2 arms (38%) P G
Rayes (56) Ceftriaxone/metronidazole 2 arms P T
Rochas (57) Cefotaxime P T
Rodriguez-Roldan (58) - P T(or N)
Rolando (59) Cefuroxime P T
Rolando (60 Ceftazidime/flucloxacillin 2 arms P T

Ruza (61) - P T
Sanchez-Garcia (62) Ceftriaxone P G
Schardey (63) Cefotaxime 2 arms Pb T
Smith (64) Cefotaxime/ampicillin 2 arms P T

Stoutenbeek (65) Cefotaxime 2 arms P T
Stoutenbeek (66) Cefotaxime P T
Tetteroo (67) Cefotaxime P T
Ulrich (68) Trimetoprim P Nor
Unertl (69) - Pb G

Verwaest (70) Cefotaxime P T
 Ofloxacin Ofloxacin
Wiener72 - P G
Winter (72) Ceftazidime P T
Zobel (73) Cefotaxime P G
Zwaveling (74) Cefotaxime/tobramycin 2 arms P T

Authors Enteral

 Yeasts MRSA Site

Abele-Horn (21) A O, -
Aerdts (22) A O,I -
Arnow (23) Ny O,I -
Barrette (24) A -, I
Bergmans (25) - Van O, -
Bion (26) A O,I -
Blair (27) A O,I -
Boland (28) Ny O,I -
Bouter (29) - O, -
Brun-Buisson (30) - -, I
Camus (31) - O,I -
Cerra (32) Ny -, I
Cockerill (33) Ny O,I -
de la Cal (34) A O,I -
de Jonge (35) A O,I -
Ferrer (36 A O,I
Finch (37) A O,I
Flahertye (38) Ny O,I
Gastinne (39) A O,I
Gaussorgues (40) A Van -, I
Georges (41) A O,I
Gosneyl (42) A O,I
Hammond (43) A O,I
Hellinger (44) Ny 1
Jacobs (45) A O,I
Kerver (46) A O,I
Korinek (47) A Van O,I
Krueger (48) - Van 1
Laggner (49) A O'_
 2 arms
Lingnau (50) A O,I
 A O,I
Luiten (51) A O,I
Palomar (52) A 1
Pneumatikos (53) A O'_
Pugin (54) - Van O'_
Quinio (55) A O,I
Rayes (56) A -, I
Rochas (57) A O,I
Rodriguez-Roldan (58) A O'_
Rolando (59) A, Clo Mup O,I
Rolando (60 A O,I
 2 arms
Ruza (61) Ny -, I
Sanchez-Garcia (62) A O,I
Schardey (63) A Van - ,I
Smith (64) A O,I

Stoutenbeek (65) A O,I
Stoutenbeek (66) A O,I
Tetteroo (67) A O,I
Ulrich (68) A O,I
Unertl (69) A 1
 (only O)
Verwaest (70) A O,I
 O,I
Wiener72 Ny O,I
Winter (72) A O,I
Zobel (73) A O,I
Zwaveling (74) A O,I

AGNB=aerobic Gram-negative bacilli, MRSA=methicillin-resistant,
Scaphylococcus aureus, SDD=selective decontamination of the
digestive tract, C=control, A=amphotericin B, Cipro=ciprofloxacin,
Cie=clotrimazole, G=gentamicin, Mup= mupirocin, Nat=nalidixic
acid, Neo=neomycin, N=netilmicin, Nor=norfloxacin, Ny=nystatin,
P=polymyxin E, Pb=polymyxin B, T=tobramycin, Van=vancomycin,
O=oropharynx, I=intestine, MU=million units.

TABLE 2
Meta-analysis of RCTs on the effect of SDD on Gram-negative and
Gram-positive bacterial carriage and infections

Endpoints No. RCTs No. patients No. events
 SDD C SDD C
Gram-negative

 Oropharyngeal carriage 20 1789 1758 141 536

 Rectal carriage 15 971 971 69 346

 Overall infections 8 451 472 20 89

 LRTI 14 759 750 24 170

 Bloodstream infection 19 1134 1136 23 87

Gram-positive

 Oropharyngeal carriage 12 1129 1093 62 110

 Rectal carriage 6 410 403 42 64

 Overall infections 4 266 252 25 26

 LRTI 14 585 593 49 80

 Bloodstream infectons 19 1134 1146 104 103

Endpoints OR (95% CI) P

Gram-negative

 Oropharyngeal carriage 0.13 (0.07-0.23) <0.001

 Rectal carriage 0.15 (0.07-0.31) <0.001

 Overall infections 0.17 (0.10-0.28) <0.01

 LRTI 0.11 (0.06-0.20) <0.001

 Bloodstream infection 0.35 (0.21-0.67) <0.001

Gram-positive

 Oropharyngeal carriage 0.55 (0.30-1.02) 0.06

 Rectal carriage 0.53 (0.12-2.43) 0.41

 Overall infections 0.76 (0.41-1.40) 0.30

 LRTI 0.52 (0.34-0.78) 0.0016

 Bloodstream infectons 1.03 (0.75-1.41) 0.85

RCTs=randomised controlled trials, SDD= selective decontamination
of the digestive tract, C= controls, OR= odds ratio,
CI=confidence interval, LRTI= lower respiratory tract infection.
The Q and [I.sup.2] tests for heterogeneity were not significant
in all comparisons.

TABLE 3

Subgroup analysis of carriage and infections due to Gram-negative
bacteria

Endpoints No. RCTs No. patients
 SDD C

Oropharyngeal carriage

 Parenteral plus enteral 15 1425 1402

 Enteral only 5 395 387

 Randomisation adequate 5 372 377

 Randomisation inadequate 15 1417 1381

 Blinded 7 738 731

 Not blinded 13 1051 1027

 High quality 13 1323 1280

 Low quality 7 466 470

Rectal carriage

 Parenteral plus enteral 10 718 709

 Enteral only 5 253 262

 Randomisation adequate 4 212 220

 Randomisation inadequate 11 759 751

 Blinded 7 596 596

 Not blinded 8 375 375

 High quality 7 467 467

 Low quality 8 504 504

Overall infections

 Parenteral plus enteral 6 367 344

 Enteral only 2 105 107

 Randomisation adequate 3 224 223

 Randomisation inadequate 5 248 218

 Blinded 1 131 140

 Not blinded 7 341 311

 High quality 2 189 170

 Low quality 6 283 281

 Successfully decontaminated 2 106 68

 Not successfully decontaminated 2 140 143

LRTI

 Parenteral plus enteral 11 609 622

 Enteral only 3 130 128

 Randomisation adequate 3 139 134

 Randomisation inadequate 11 600 616

 Blinded 2 90 89

 Not blinded 12 649 661

 High quality 5 481 494

 Low quality 9 258 256

 Successfully decontaminated 9 447 451

 Not successfully decontaminated 2 73 72

Bloodstream infections

 Parenteral plus enteral 17 1028 1043

 Enteral only 2 106 103

 Randomisation adequate 4 194 190

 Randomisation inadequate 15 940 996

 Blinded 1 76 72

 Not blinded 18 1058 1074

 High quality 7 304 275

 Low quality 12 830 871

 Successfully decontaminated 9 474 447

 Not successfully decontaminated 2 57 63

Endpoints No. events OR (95% CI) P
 SDD C

Oropharyngeal carriage

 Parenteral plus enteral 110 464 0.09 (0.04-0.18) <0.001

 Enteral only 27 73 0.39 (0.19-0.81) 0.011

 Randomisation adequate 21 88 0.21 (0.08-0.60) 0.004

 Randomisation inadequate 120 448 0.11 80.05-0.21) <0.001

 Blinded 41 228 0.14 (0.06-0.35) <0.001

 Not blinded 100 308 0.12 (0.06-0.25) <0.001

 High quality 110 338 0.15 (0.08-0.28) <0.001

 Low quality 31 198 0.11 (0.06-0.19 <0.001

Rectal carriage

 Parenteral plus enteral 50 297 0.11 (0.53-0.24) <0.001

 Enteral only 19 49 0.26 (0.05-1.35) 0.11

 Randomisation adequate 21 61 0.19 (0.04-1.03) 0.054

 Randomisation inadequate 48 286 0.13 (0.06-0.29) <0.001

 Blinded 53 231 0.16 (0.06-0.44) <0.001

 Not blinded 16 115 0.12 (0.03-0.43) <0.001

 High quality 30 101 0.31 (0.11-0.87) 0.026

 Low quality 39 245 0.08 (0.04-0.16) <0.001

Overall infections

 Parenteral plus enteral 18 78 0.15 (0.09-0.27) <0.001

 Enteral only 2 11 0.19 (0.05-0.83) 0.027

 Randomisation adequate 11 45 0.19 (0.09-0.39) <0.001

 Randomisation inadequate 9 44 0.13 (0.06-0.30) <0.001

 Blinded 5 19 0.25 (0.09-0.26) NE

 Not blinded 15 70 0.14 (0.08-0.26) <0.001

 High quality 7 35 0.10 (0.01-0.75) 0.025

 Low quality 13 54 0.18 (0.10-0.35) <0.001

 Successfully decontaminated 6 9 0.08 (0.01-0.43) 0.003

 Not successfully
 decontaminated 3 18 0.16 (0.05-0.54) 0.003

LRTI

 Parenteral plus enteral 9 127 0.07 (0.04-0.13) <0.001

 Enteral only 15 43 0.28 (0.11-0.68) 0.005

 Randomisation adequate 13 33 0.33 (0.16-0.70) = 0.004

 Randomisation inadequate 11 137 0.08 (0.04-0.14) <0.001

 Blinded 13 35 0.15 (0.01-2.45) 0.18

 Not blinded 11 135 0.08 (0.04-0.14) <0.001

 High quality 8 81 0.11 (0.05-0.21) <0.001

 Low quality 16 89 0.07 (0.02-0.37) <0.001

 Successfully decontaminated 19 124 0.08 (0.03-0.21) <0.001

 Not successfully
 decontaminated 1 16 0.09 (0.02-0.54) 0.008

 Bloodstream infections

 Parenteral plus enteral 23 80 0.36 (0.22-0.60) -0.001

 Enteral only 0 7 0.08 (0.01-1.48) 0.089 *

 Randomisation adequate 0 19 0.05 (0.01-0.45) 0.007

 Randomisation inadequate 23 68 0.39 (0.23-0.64) -0.001

 Blinded 0 6 0.03 (0.01-1.92) NE

 Not blinded 23 81 0.36 (0.22-0.59) -0.001

 High quality 6 15 0.61 (0.23-1.67) 0.34

 Low quality 17 72 0.29 (0.15-0.54) -0.001

 Successfully decontaminated 5 29 0.35 (0.12-0.98) 0.045

 Not successfully
 decontaminated 2 1 0.03 (0.03-83.9) 0.82

RCTs=randomised controlled trials, SDD=selective decontamination of the
digestive tract, C= control, OR=odds ratio, CI= confidence interval,
LRTI=lower airway infection. NE=not evaluated as only one study was
included. The Q and h tests for heterogeneity were not significant
in all comparisons except for * where [I.sup.2] was greater than 50%.

TABLE 4
Subgroup analysis of carriage and infections due to Gram-positive
bacteria

Endpoints No. RCTs No. patients
 SDD C
Oropharyngeal carriage

 Parenteral plus enteral 8 868 837

 Enteral only 4 261 256

 Randomisation adequate 2 199 198

 Randomisation inadequate 10 930 895

 Blinded 3 248 240

 Not blinded 9 881 853

 High quality 9 988 949

 Low quality 3 141 144

Rectal carriage

 Parenteral plus enteral 3 160 157

 Enteral only 3 250 246

 Randomisation adequate 2 145 137

 Randomisation inadequate 4 265 266

 Blinded 3 183 178

 Not blinded 3 227 225

 High quality 4 299 288

 Low quality 2 111 115

Overall infections

 Parenteral plus enteral 3 226 213

 Enteral only 1 40 39

 Randomisation adequate 1 131 140

 Randomisation inadequate 3 135 112

 Blinded 1 131 140

 Not blinded 3 135 112

 High quality 2 189 170

 Low quality 2 77 82

LRTI

 Parenteral plus enteral 11 455 465

 Enteral only 3 130 128

 Randomisation adequate 3 115 114

 Randomisation inadequate 11 470 479

 Blinded 2 90 89

 Not blinded 12 504 495

 High quality 6 271 271

 Low quality 8 314 322

Bloodstream infection

 Parenteral plus enteral 17 1028 1043

 Enteral only 2 106 103

 Randomisation adequate 3 169 165

 Randomisation inadequate 16 965 981

 Blinded 1 76 72

 Not blinded 18 1058 1074

 High quality 7 304 275

 Low quality 12 830 871

Endpoints No. events OR (95% CI) P
 SDD C

Oropharyngeal carriage 46 82 0.52 (0.25-1.10) 0.088

 Parenteral plus enteral 16 28 0.65 (0.17-2.48) 0.52

 Enteral only 9 40 0.16 (0.07-0.35) <0.001

 Randomisation adequate 53 70 0.66 (0.37-1.79) 0.16

 Randomisation inadequate 9 40 0.16 (0.08-0.36) <0.001

 Blinded 53 70 0.65 (0.35-1.21) 0.18

 Not blinded 53 93 0.56 (0.25-1.26) 0.16

 High quality 9 17 0.50 (0.21-1.18) 0.11

 Low quality

Rectal carriage

 Parenteral plus enteral 42 60 0.72 (0.10-5.30) 0.75

 Enteral only 0 4 0.25 (0.01-4.15) 0.33

 Randomisation adequate 5 0 7.01 (0.27-185.39) 0.24

 Randomisation inadequate 37 64 0.33 (0.07-1.56) 0.16

 Blinded 5 4 1.06 (0.03-41.73) 0.98

 Not blinded 37 60 0.41 (0.07-2.34) 0.32

 High quality 5 4 1.04 (0.07-15.69) 0.98

 Low quality 37 60 0.38 (0.05-2.74) 0.33

Overall infections

 Parenteral plus enteral 22 20 0.85 (0.44-1.66) 0.64

 Enteral only 3 6 0.45 (0.10-1.93) NE

 Randomisation adequate 4 5 0.85 (0.22-3.24) NE

 Randomisation inadequate 21 21 0.74 (0.37-1.46) 0.39

 Blinded 4 5 0.85 (0.22-3.24) NE

 Not blinded 21 21 0.74 (0.37-1.46) 0.39

 High quality 15 13 0.71 (0.31-1.63) 0.42

 Low quality 10 13 0.81 (0.31-2.10) 0.67

LRTI

 Parenteral plus enteral 24 38 0.59 (0.34-1.02) 0.061

 Enteral only 25 42 0.59 (0.40-0.89) 0.011

 Randomisation adequate 23 36 0.47 (0.24-0.91) 0.024

 Randomisation inadequate 26 44 0.55 (0.32-0.93) 0.025

 Blinded 22 36 0.44 (0.23-0.86) 0.017

 Not blinded 27 44 0.57 (0.34-0.96) 0.033

 High quality 36 53 0.51 (0.31-0.85) 0.01

 Low quality 13 27 0.53 (0.27-1.04) 0.066

Bloodstream infection

 Parenteral plus enteral 84 90 0.94 (0.66-1.33) 0.071

 Enteral only 20 13 1.63 (0.76-3.48) 0.21

 Randomisation adequate 27 28 0.74 (0.22-2.46) 0.62

 Randomisation inadequate 77 75 1.05 (0.74-1.50) 0.77

 Blinded 13 7 1.65 (0.64-4.26) NE

 Not blinded 91 95 0.97 (0.69-1.36) 0.87

 High quality 28 19 1.36 (0.72-2.56) 0.35

 Low quality 76 84 0.94 (0.65-1.37) 0.75

RCTs=randomised controlled trial, SDD=selective decontamination of the
digestive tract, C=controls; OR=odds ratio, CI=confidence interval,
LRTI=lower respiratory tract infection, NE=not evaluated as only one
study was included. The Q and I[sup.2] tests for heterogeneity were not
significant in all comparisons.
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Author:Silvestri, L.; Van Saene, H.K.F.; Casarin, A.; Berlot, G.; Gullo, A.
Publication:Anaesthesia and Intensive Care
Geographic Code:4EUIT
Date:May 1, 2008
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